Abstract

Zika virus is a mosquito-borne flavivirus discovered in Africa in 1947. Most persons with Zika virus infection are asymptomatic; symptoms when present are generally mild and include fever, maculopapular rash, arthralgia, and conjunctivitis. Since early 2015, Zika virus has spread rapidly through the Americas, with local transmission identified in 31 countries and territories as of February 29, 2016, including several US territories. All age groups are susceptible to Zika virus infection, including children. Maternal–fetal transmission of Zika virus has been documented; evidence suggests that congenital Zika virus infection is associated with microcephaly and other adverse pregnancy and infant outcomes. Perinatal transmission has been reported in 2 cases; 1 was asymptomatic, and the other had thrombocytopenia and a rash. Based on limited information, Zika virus infection in children is mild, similar to that in adults. The long-term sequelae of congenital, perinatal, and pediatric Zika virus infection are largely unknown. No vaccine to prevent Zika virus infection is available, and treatment is supportive. The primary means of preventing Zika virus infection is prevention of mosquito bites in areas with local Zika virus transmission. Given the possibility of limited local transmission of Zika virus in the continental United States and frequent travel from affected countries to the United States, US pediatric health care providers need to be familiar with Zika virus infection. This article reviews the Zika virus, its epidemiologic characteristics, clinical presentation, laboratory testing, treatment, and prevention to assist providers in the evaluation and management of children with possible Zika virus infection.

Abbreviations:

CDC —

Centers for Disease Control and Prevention

DEET —

N,N-Diethyl-meta-toluamide

IgM —

immunoglobulin M

PRNT —

plaque reduction neutralization test

RT-PCR —

reverse transcription polymerase chain reaction

Zika virus is a mosquito-borne virus in the Flavivirus genus that is closely related to dengue, West Nile, and yellow fever viruses. After its discovery in 1947,1 Zika virus was known to cause sporadic cases of mild, self-limited illness in persons living in Africa and Asia. The first widespread outbreak of Zika virus infection was recognized on Yap Island, Federated States of Micronesia, in 20072; outbreaks in Southeast Asia and the western Pacific followed, including a large outbreak in French Polynesia in 2013–2014.3 The virus in the French Polynesia outbreak has been phylogenetically linked to the virus that emerged in Brazil in May 2015,4 when the first local transmission of Zika virus in the Americas was reported.5 Zika virus quickly spread throughout the country, with an estimated 440 000 to 1 300 000 suspected cases by the end of 2015.6 In October 2015, the Brazilian Ministry of Health reported increasing numbers of infants born with microcephaly.7 From October 2015 through February 2016, >5000 infants with suspected microcephaly had been reported, with confirmation of microcephaly in about one-third of the first 1300 infants who underwent evaluation.8 Guillain-Barré syndrome has also been described in conjunction with Zika virus infection.9 Although there is increasing supportive evidence, a causal relationship has not yet been established between Zika virus infection and either microcephaly or Guillain-Barré syndrome.

Given the widespread nature of the Zika virus epidemic in the Americas, the temporally associated increase in microcephaly and Guillain-Barré syndrome in Brazil, and the retrospective findings of a cluster of microcephaly and neurologic disorders associated with Zika virus in French Polynesia, the World Health Organization declared Zika virus a Public Health Emergency of International Concern on February 1, 2016.10 Local transmission was reported in 31 countries and territories in the Americas as of February 29, 2016, including some US territories.11 Based on the distributions of its primary mosquito vector, Aedes aegypti, and another possible vector, Aedes albopictus, local Zika virus transmission is possible in the continental United States.12

Because Zika virus transmission has been documented in many countries, pediatric health care providers in the United States are likely to become involved in the evaluation and management of infants and children with possible Zika virus infection as well as discussions regarding its prevention. To assist pediatric providers, the present article reviews information on Zika virus, its epidemiologic characteristics, clinical presentation in children, laboratory testing, treatment, and methods of prevention.

Zika Virus

Vectors

Humans and nonhuman primates are the likely principal vertebrate hosts for Zika virus, which is primarily transmitted to humans through the bite of mosquitoes, most commonly Aedes aegypti and possibly Aedes albopictus.12 Within the continental United States, these Aedes species are primarily found in the South, Midwest, and the Great Plains, with small pockets in the Southwest and California (http://www.cdc.gov/chikungunya/resources/vector-control.html). Aedes species mosquitoes are aggressive daytime feeders. They live in and around human households, are difficult to eradicate, and are able to reproduce in small water containers.13

Routes of Transmission

Although mosquito-borne transmission is the main route of exposure, Zika virus infection has also been reported to occur via laboratory exposure14 and sexual transmission.15 Maternal–fetal transmission during pregnancy has been well documented,16–22 and intrapartum transmission has also been reported.23 Other flaviviruses have been transmitted via breast milk,24–26 but no cases of Zika virus infection associated with breastfeeding have been reported. Zika virus RNA can be present in breast milk.23However, based on current evidence, the potential risk of Zika virus transmission through breast milk is outweighed by the known benefits of breastfeeding.27 Although Zika virus RNA has been found in saliva28 and urine,29 no evidence exists that Zika virus can be transmitted through these routes.

Zika Virus Infection

Most persons with Zika virus infection are asymptomatic.2 Among those with symptoms, the illness is generally mild and self-limited. Features most often observed include maculopapular rash, fever, arthralgia, and nonpurulent conjunctivitis; symptoms typically last several days to 1 week.30 The incubation period for Zika virus in humans is unknown but is believed to be similar to that of other flaviviruses, in the range of 3 to 14 days.31 All age groups are at risk for Zika virus infection; in the Yap Island outbreak, the attack rate for symptomatic Zika virus disease among children (<19 years of age) was lower than that for adults.2

Clinical Features

Fetal

Although maternal–fetal transmission of Zika virus during pregnancy has been documented,18–22 the incidence of congenital Zika virus infection and the frequency of adverse outcomes among pregnancies infected with Zika virus are unknown. Although microcephaly is the adverse infant outcome for which there is the most evidence, information on the health effects associated with congenital Zika virus infection is limited. Since Zika virus emerged in Brazil, >5000 newborns with suspected microcephaly have been reported, although the number of cases is likely to be lower when a full investigation is completed.8 Because no standard definition exists for microcephaly, monitoring its prevalence has been challenging; studies have used different cutoffs (>2 or 3 SDs below the mean for gestational age and gender or below the 3rd or 5th percentile).32 The number of suspected cases with microcephaly reported to Brazil’s Ministry of Health over recent months is markedly higher than the 150 to 200 cases per year previously reported.33 Some have questioned whether this increase might be due to misdiagnosis related to different cutoffs or overreporting related to increased awareness of the possible association with Zika virus.34 These questions have led investigators to call for standardized measurement of head circumference and use of appropriate growth standards to improve surveillance of microcephaly that might be associated with Zika virus.32

Reports of Laboratory-Confirmed Congenital Zika Virus Infection Cases and Their Clinical Findings, Brazil and the United States, 2015–2016

Pathologic analyses of some of the aforementioned infants and fetuses have provided insight into the pathogenesis of congenital Zika virus infection.18,19 In 1 study, Zika virus RNA and antigens were detected on pathologic analysis of brain tissues from 2 newborns with microcephaly and in placental tissues from 2 early miscarriages.18 In the newborns, detection of Zika virus RNA by RT-PCR and histopathologic changes of infection were limited to the brain. In another autopsy performed after a pregnancy termination, Zika virus, as evidenced by RT-PCR, immunofluorescence, and electron microscopy, was present only in the brain; no other fetal organs were affected.19 Placental calcifications and a low placental–fetal weight ratio were also seen. These findings have led investigators to suggest that Zika virus is neurotropic and might also cause placental damage.

Reports of infants with suspected congenital Zika virus infection provide additional information (Table 2). Clinical information on the first 35 infants to be enrolled in the Brazilian Ministry of Health microcephaly registry was recently reported.35 Although none of these infants underwent Zika virus testing, congenital Zika virus infection was suspected on the basis of all mothers residing in areas with local transmission and three-quarters reporting a rash during the first or second trimester of pregnancy. In addition to microcephaly, postnatal neuroimaging results revealed calcifications, ventriculomegaly, and neuronal migration disorders, and the infants had abnormal neurologic findings (eg, hypertonia, hyperreflexia, irritability, seizures). Findings of microcephaly, cortical and subcortical atrophy, and redundant scalp skin in some infants are suggestive of fetal brain disruption sequence, in which disruption of fetal brain growth leads to skull collapse.36 Other findings included talipes and arthrogryposis, likely to be secondary to neurologic involvement. Ophthalmologic abnormalities (including chorioretinal atrophy, optic nerve hypoplasia and pallor, and lens subluxation) have been described in infants born with microcephaly who are suspected of having congenital Zika virus infection.37–39

Because information on infants with congenital Zika virus infection is limited, it is unclear whether other central nervous system manifestations beyond microcephaly might occur (eg, cognitive impairment in the absence of microcephaly or structural abnormalities). Furthermore, while Zika virus seems to exhibit neurotropism,18,19 involvement of other organ systems cannot be excluded.

Vertical transmission of other flaviviruses seems to occur rarely; this transmission has not been associated with an increased risk for congenital anomalies. Although 1 infant born to a mother with West Nile virus encephalitis at 27 weeks’ gestation had cerebral destruction and chorioretinitis,40 rates of birth defects in a West Nile virus pregnancy registry were not significantly increased compared with baseline,41 and a follow-up study suggested no adverse effects of West Nile virus on development.42 Prenatal dengue virus infection does not seem to increase the risk for congenital anomalies.43 Maternal–fetal transmission of other non-flavivirus infections (eg, rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, Toxoplasma gondii) has been associated with microcephaly.44 Other manifestations of these congenital infections include various brain abnormalities (eg, intracranial calcifications, hydrocephalus), eye abnormalities (eg, cataracts, glaucoma, chorioretinitis), and hearing impairment.

Although no information on long-term outcomes of infants with microcephaly related to Zika virus infection is available, head circumference at birth generally reflects intrauterine brain growth. Based on microcephaly due to other causes, infants with severe microcephaly associated with Zika virus infection are likely to be at risk for long-term adverse outcomes, including seizures, cognitive impairment, and hearing and vision impairments.45 Congenital microcephaly can be associated with prenatal exposure to other infectious and noninfectious (eg, alcohol, mercury) agents and with genetic conditions; evaluation for other etiologies needs to be completed when congenital Zika virus infection is excluded.

Neonatal

To date, we are aware of 2 reports of presumed perinatally acquired Zika virus infection.23 One mother developed pruritic rash 2 days before delivery; her infant remained asymptomatic. The second mother developed fever, myalgia, and pruritic rash 3 days after delivery; her infant developed thrombocytopenia and a transient rash 4 days after birth. Both mother–infant pairs tested positive for Zika virus RNA in serum postnatally and were discharged in good health. Both mothers were likely to have been viremic during labor, raising the possibility of intrapartum transmission. Postnatal transmission via breast milk or saliva was also possible, but transmission via these routes has not been reported in the literature.

Perinatal transmission of other flaviviruses has been associated with severe illness. Neonates who acquire dengue virus infection through presumed perinatal transmission have developed fever, thrombocytopenia, and hemorrhage.43 A range of illness severity was seen among 3 infants with West Nile virus infection transmitted during the perinatal period (1 each with rash, West Nile virus encephalitis, and West Nile virus meningitis).41 The spectrum of illness in neonates who acquire Zika virus perinatally is unknown.

Infant and Child

Although data are limited, most children infected with Zika virus through mosquito bites have been mildly affected or asymptomatic, similar to adults. During the Yap Island outbreak, among those with symptoms (age range, 1–76 years), fever, macular or papular rash, arthralgia, and conjunctivitis were most frequently observed. Six publications describe clinical features of Zika virus infection in 10 children ranging in age from 3 to 16 years (Table 3).46–51 Illness duration was <1 week, and common manifestations included fever, malaise, headache, and myalgia. Seven of 10 children described in case reports presented with gastrointestinal symptoms; whether these symptoms occur more frequently in children than in adults is unknown. Although not seen in the 7 children for whom information is available, rash has been prominent in Zika virus outbreaks.2,6,52 The rash associated with adult Zika virus infection is characterized as pruritic, maculopapular, originating on the trunk, and spreading to involve the face and extremities, and lasting for 2 to 14 days.2,23,53

Complications of pediatric Zika virus infection have rarely been reported. Two deaths possibly associated with Zika virus disease among adolescents have been reported. The first, a 16-year-old Brazilian girl, was hospitalized with headache, nausea, and petechiae.7,54 Zika virus infection was confirmed by RT-PCR; dengue and chikungunya virus test results were unavailable. No further details are available. The second pediatric death occurred in a 15-year-old Colombian girl with sickle cell disease (hemoglobin SC), with no history of vaso-occlusive crises, who was hospitalized with abdominal pain, tachycardia, and tachnypnea.51 She developed severe acute respiratory distress syndrome, hemothorax, and splenic sequestration. Results of RT-PCR testing were positive for Zika virus RNA; test results for dengue, yellow fever, and chikungunya viruses and malaria were also negative. Deaths related to Zika virus infection in children were not reported after outbreaks on Yap Island or in French Polynesia.2,9 Among the 38 cases of Guillian-Barré syndrome during the French Polynesia outbreak, none occurred among children.9 Guillain-Barré syndrome and acute disseminated encephalomyelitis occurred in 6 patients with laboratory-confirmed Zika virus infection in Brazil (age range, 2–57 years)6; additional details were not provided. Whether these neurologic conditions are caused by Zika virus infection is currently unknown.

Diagnosis

The Centers for Disease Control and Prevention (CDC) has released updated interim guidelines for health care providers caring for infants and children with possible Zika virus infection.27 Clinical features of Zika virus infection can resemble common childhood illnesses, which might make diagnosing Zika virus infection in infants and children challenging. Because Zika virus antibody tests can cross-react with those for other flaviviruses,55,56 laboratory test results must be interpreted with caution. Based on current recommendations, infants and children with epidemiologic risk factors and manifestations of Zika virus infection should undergo Zika virus testing (http://www.cdc.gov/zika/hc-providers/diagnostic.html). Testing will allow further characterization of the clinical manifestations associated with pediatric Zika virus disease and inform public health interventions, such as targeted vector control in areas of newly established local transmission.

Infants born to mothers who traveled to or resided in areas with local Zika virus transmission during pregnancy, or who are born to mothers who had sexual contact with male partners who traveled to or resided in these areas, might be at risk for congenital Zika virus infection. In these cases, the decision to test is informed by the following: (1) presence of microcephaly or intracranial calcifications based on prenatal or postnatal ultrasound; and (2) the mother’s prenatal or postnatal Zika virus test results. All infants with the aforementioned epidemiologic risk factors and microcephaly or intracranial calcifications should be tested for Zika virus, regardless of maternal test results. For infants without microcephaly or intracranial calcifications, testing is indicated for infants born to mothers with positive or inconclusive Zika virus test results; those born to mothers with negative test results or who were not tested should receive routine care. Health care providers should exercise clinical judgment when evaluating infants with other abnormalities (eg, hearing loss) born to mothers with travel to or reside in an area with local Zika virus transmission, or who are born to mothers who have had sexual contact with partners who traveled to or resided in these areas. In these scenarios, clinicians can consider testing the mother for Zika virus infection to inform infant evaluation.

Perinatal transmission of Zika virus infection should be suspected in an infant in the first 2 weeks of life if the infant’s mother traveled to or resided in an affected area within 2 weeks of delivery and the infant has at least 2 of the following: fever, rash, conjunctivitis, or arthralgia. Although arthralgia is difficult to assess in infants and young children, suggestive findings include refusal to move an affected limb, pain on palpation or with passive range of motion, abnormal gait or limp in ambulatory children, and irritability. Neonates born to mothers with manifestations of Zika virus disease around the time of delivery should be monitored for Zika virus illness; both mother and infant should be tested if such illness develops.

Mosquito-borne transmission of Zika virus infection should be suspected in children who (1) have traveled to or resided in an affected area within the past 2 weeks; and (2) have at least 2 of the following: fever, rash, conjunctivitis, or arthralgia. Testing for other flaviviruses is informed by travel history. Adolescents might also be exposed to Zika virus through sexual contact with a male partner who traveled to or resided in an affected area. Health care providers caring for patients with possible sexual exposure to Zika virus should refer to the CDC’s interim guidelines.15

At this time, no commercially available US Food and Drug Administration–cleared diagnostic tests for Zika virus are available. Testing is arranged through state, local, and territorial health departments and is performed at the CDC and some state health departments. Arboviruses, including Zika virus, are nationally notifiable diseases.

Laboratory Testing

Molecular Diagnostics

Given its high sensitivity and specificity for detecting Zika virus,56 RT-PCR testing of serum within the first week of illness is preferred for laboratory confirmation of Zika virus infection.57 RT-PCR may also be used on tissue specimens (eg, placenta, autopsy specimens) in specialized laboratories. A positive RT-PCR test result indicates Zika virus infection. However, RT-PCR can only detect virus in serum during viremic periods, estimated to occur during the first week of illness; a negative result from serum collected on day 5 of illness or later does not exclude infection.

Serology

Zika virus immunoglobulin M (IgM) antibodies have been detected as early as 4 days after illness onset. Based on experience with other flaviviruses, Zika virus IgM antibodies are expected to be present beginning 4 days after illness onset and persist for at least 12 weeks.57,58 Because cross-reactivity between Zika and dengue virus IgM assays can occur, IgM-positive results should be followed by plaque reduction neutralization tests (PRNT).57 Immunoglobulin G assays are less specific for arboviral antibodies than IgM assays.59

PRNT

When serologic test results are equivocal, PRNT can measure virus-specific neutralizing antibodies, which may be useful in discriminating Zika virus from other flaviviruses. However, because cross-reactivity is more likely to occur in patients with previous flavivirus exposure through natural infection or immunization (eg, yellow fever vaccine), PRNT results from these patients must be interpreted cautiously.57

Treatment

Currently, no specific treatment of Zika virus infection is available. Supportive care consists of rest, fluids, and symptomatic treatment. Acetaminophen and antihistamines have been used to treat fever and pruritus, respectively.60 Aspirin and other salicylates should be avoided in children due to an association with Reye’s syndrome, and nonsteroidal antiinflammatory drugs should be used cautiously in children with dehydration and avoided in infants aged <6 months due to inadequate information on pharmacokinetics and potential for nephrotoxicity.61 Nonsteroidal antiinflammatory drugs can also increase the risk of hemorrhagic complications in patients with dengue virus infection and thus should be avoided until dengue infection has been excluded.62 To reduce the risk of transmission to others, infected patients should take precautions to prevent mosquito bites, especially during the first week of illness when they are likely to be viremic.

Prevention

No vaccine is available to prevent Zika virus infection. Sexual transmission of Zika virus from male partners has been documented, although it is unknown how long semen remains infectious. Thus, male subjects who reside in or have traveled to an area of active Zika virus transmission and have a pregnant partner should abstain from sexual activity or consistently and correctly use condoms during sex for the pregnancy duration.15 If either partner is concerned about sexual transmission to a nonpregnant partner, the male subject might also consider abstaining from sexual activity or using condoms consistently and correctly during sex. Additional information is available in CDC’s interim guidelines for prevention of sexual transmission.

Because of the possible risk for Zika virus transmission associated with blood transfusions,63 the US Food and Drug Administration issued guidance on February 16, 2016, regarding deferral of blood donations from persons who have traveled to areas with active Zika virus transmission, have potential exposure to the virus, or have had a confirmed Zika virus infection (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm486359.htm).

Based on CDC interim travel guidance (http://wwwnc.cdc.gov/travel/notices), pregnant women should postpone travel to areas with ongoing Zika virus transmission. Pregnant women who must travel to 1 of these areas should talk with their health care provider first and strictly follow steps to prevent mosquito bites during their trip. The CDC recommends that all persons who travel to areas with local transmission protect themselves from mosquito bites. Zika virus prevention centers on personal avoidance of mosquito bites and reducing mosquito populations.64 Personal avoidance measures include staying in buildings with air-conditioning or with window and door screens, wearing full-length garments and socks, and using mosquito repellent.62 Permethrin-treated clothing can repel mosquitoes. Bed nets are advised for travel to areas in which accommodations are not adequately screened or air-conditioned.

The CDC recommends the use of insect repellents registered by the Environmental Protection Agency according to the instructions on the label.62 Products containing N,N-Diethyl-meta-toluamide (DEET), picaridin, oil of lemon eucalyptus, or ethyl butylacetylaminopropionate provide protection from mosquito bites. Higher DEET concentrations are associated with longer duration of action. Efficacy plateaus at a concentration approaching 50%, and the maximum recommended concentration for infants and children is 30%. Products containing DEET should not be used on children aged <2 months; this group can be protected by use of mosquito netting. Mosquito repellents containing oil of lemon eucalyptus (p-Menthane-3,8-diol) should not be used in children aged <3 years. Only adults should handle repellents, which should be applied judiciously to children’s exposed skin, avoiding the hands, eyes, mouth, and broken or irritated skin. Skin treated with mosquito repellent should be washed with soap and water after returning indoors, especially before meals. Combination products that include both mosquito repellent and sunscreen should be avoided because sunscreen may need to be applied more frequently and in larger amounts than needed for adequate mosquito bite protection. Sunscreen, when used, should be applied before repellent. Insect repellents should not be applied in enclosed areas or near food or underneath clothing. More information on the prevention of mosquito-borne illnesses can be found at: http://www.cdc.gov/zika/prevention/ and http://www.epa.gov/insect-repellents/using-repellent-products-protect-against-mosquito-borne-illnesses.

Resources

Information on Zika virus and its consequences is rapidly accruing. Readers may find the following resources helpful to stay abreast of developments:

Summary

Less than 1 year after identification of Zika virus in Brazil, transmission is now widespread throughout much of the Americas. Local transmission of Zika virus has been established in US territories, and in addition to travel-associated cases, limited local transmission is likely to occur in some parts of the continental United States. Infants and children living in or traveling to affected areas are at risk for contracting Zika virus, as are neonates born to women who reside in or travel to affected areas where they may be exposed through mosquitoes carrying the virus. Sexual transmission of Zika virus has been reported, and women who have unprotected sexual contact with a male partner who resides in or has traveled to an area of Zika virus transmission are also at risk for infection. Congenital Zika virus infection appears to be associated with microcephaly and possibly other birth defects of the brain and eye. Based on limited data, it seems that most infants and children who contract Zika virus via mosquitoes have no or mild illness, similar to findings in adults. To provide guidance to caregivers and patients, and to evaluate and manage infants and children potentially infected with Zika virus, pediatric health care providers need to know the signs and symptoms, appropriate laboratory tests, and clinical guidelines. Updated information on Zika virus and children can be found at: www.cdc.gov/Zika.

Acknowledgments

We express our gratitude to the American Academy of Pediatrics for their thoughtful comments in preparing this article and Dr Michael Cannon at the CDC for translating Portuguese documents.